Trifluoromethylthiaxanthene and -xanthene derivatives



3,192,204 TRIFLUOROMETHYLTEHAXANTHENE AND XANTH'ENE DERIVATIVES Paul N.Craig, Roslyn, and Charles L. Zirkle, Berwyn, Pa.,

assignors to Smith Kline & French Laboratories, Philadelphia, Pa., acorporation of Pennsylvania N Drawing. Filed Mar. 7, 136%, Ser. No.12,966 14 Claims; (Cl. 260240) This invention relats to newtrifluoromethylthiaxantheme and -xanthene derivatives which have usefulpharmacodynamic activities.

More specifically the compounds of this invention have utility astranquilizers, ataractics, antiemetics, antihistaminics, antispasmodicsand general central nervous system depressants. In addition certain ofthe compounds of this invention have utility as intermediates for thepreparation of other therapeutic compounds. 7

The novel compounds of this invention are represented by the followingbasic structural formula:

Formula I Rg-lHtfHCHr-Z a Formula II iiHoH,oH,Z

when: 7

Y represents sulfur or oxygen;

Z represents dimethylamino, N'-methyl-N-piperazinyl, N hydroxyethyl Npiperazinyl, N-acetoxyethyl-N- piperazinyl, Nhydroxyethoxyethyl-N-piperazinyl orN'-hydroxyethoxyethoxyethyl-N-piperazinyl.

By the term lower alkyl where used herein alone or in combination withother terms, groups having from 1 to 4, preferably 1 to 2 carbon atoms,are indictaed.

This invention also includes stable, pharmaceuically acceptable, acidaddition salts of the above defined bases formed with nontoxic organicand inorganic acids. Such salts are easily prepared by methods known tothe art. The base is reacted with either the calculated amount oforganic or inorganic acid in aqueous miscible, solvent such as acetoneor ethanol, with isolation of the salt by concentration and cooling oran excess of the acid in aqueous immiscible solvent, such as ethyl etheror chloroform, with thedesired salt separating directly. Exemplary ofsuch organic salts are those with maleic, fumaric,

United States Patent 0 3,192,294 Patented June 29, 1965 benzoic,ascorbic, pamoic, succinic, bismethylenesalicyclic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids as well as with the 8-halotheophyllines, for example 8-chlorotheophylline and8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids. These salts may also be preparated by the classical method ofdouble decomposition of appropriate salts which is well-known to theart.

The 10-aminoalkylidene-trifluoromethylthiaxanthenes and 9aminoalkylidene-trifiuoromethylxanthenes of this invention are preparedas shown in the following synthetic scheme:

Y\ 7 i @012; V7

rroHoH z xanthene. I

Dehydration of the above prepared intermediate is ac complished bytreatment with a mineral acid such as hydrochloric or sulfuric acid atabout 60 to 0. for a period of about one to four hours. Removal of theexcess acid gives the 1O-aminoalkylidene-trifi uoromethyl thiaxanthe-nesor 9-arninoalkyli-dene-trifluoromethylxanthenes of this invention.

These aminoalkylidene compounds, in addition to hav ing utility astranquilizers, at-aractics, .ant iernetics, antihistamines,ant-ispasnrodics and general central nervous system depressants, areuseful as intermediates in the preparation of 10aminoalkyl-trifluoromethylthiaxanthenes and the corresponding -xantheneshaving the above de scribed activity. The aminoalkylidene compounds ofthis invention are reduced by hydrogenation in the presence of ahydrogenation catalyst, such as platinum oxide or l XGILCHGHr-Z l Rs (JHzGHCHr-Z in The terms Y, R and Z are as previously defined and Xis-halogen.

The thiaxanthenones or xanthenon-es are reduced by catalytichydnogena'tion or chemically, preferably, with sodium and an alcoholsuch as for example, isobutyl or isoamyl alcohol, or a metal hydridesuch as lithium aluminum hydride, The resulting thiaxanthenes andxanthenes are alkylated with a reactive aminoalkyl ester such as ahalide,;prefera-bly chloride or bromide, or an arylsulfonate such asp-tosylate or phenylsulfonate in a suitable inert aromatic solvent suchas benzene, xylene or toluene,in which at least one of the reactants issoluble. A suitable aOid-b'inding agent may be included such as analkali metal amide, preferably sodium'or potassium amide; an alkalimetal hydride, -for example potassium or sodium hydride; an alkali metalhydroxide, for example sodium or potassium hydroxide or an alkali metalaryl or alkyl compound, preferably phenyl sodium or butyl lithium. Thepreferred method of al-kylation is to react the thiaxanthene or xanthenewith an aminoalkyl chloride or bromide with a slight excess of sodium orpotassium amide in refluxing benzene or toluene for from /2 to 24 hours,preferably 2 to ,8 hours. Certain piperazinylalkyl derivatives areprepared by further reaction of the'N-hydroxyethyl analogs to form thevarious N-substituted piperazi-nyl compounds of Formula I.

The triiluoromethylthiaxan thenone starting materials ar prepared bycondensing thiosalicylic acid with a 1-chloro-Zmitro-trifiuoromethylbenzene to giveo-(Z-nitrotrifluoromethylphenylthio)benzoic acid; reducing the nitrogroup chemically, for example with stanno-us chloride and hydrochloricacid; removing the resulting amino group by diazotization and treatmentwith ethyl alcohol and cyclizing by refluxing theo-(tritluoromethylphenylthio) benzoic acid witha mineral acid such assulfuric or polyphosphoric acid.

The trifluoromethylxanthenone starting materials are prepared from2-chloro-trifluoromethylaniline by the following steps: (1) diazotizingthe aniline and treating with potassium iodide to give.chloro-iodotnifluoromethylbenzene, (2) replacement of the iodo atom bya carboxy group via th Grigna-rd reaction, (3) condensation of theresulting 2-chloro tnifiuoromethylbenzoic acid with phenol and..(4)dehydration of the resulting Z-phenoxy-trifluoromethylbenzoic acid togive the trifluoromethylxanthen-one.

The alkylidene compounds of this invention may be present: as cis ortrans isomers as Well as mixtures of these isomers. The isomers areseparated by fractional crytallization of their acid addition salts froma suitable solvent or mixture of solvents such as, for example,acetone-ether or ethanol-ether. In addition, it will be readily apparentto one skilled in the art that certain compounds of this invention,notably those of Formula I in which R is methyl, may be present asoptical isomers. The connotation of the general formulas presentedherein is to include all isomers, the separated d or 1 optical isomersas well as the dl mixture and the separated cis or trans isomers as wellas the mixture of theseisomers.

The following examples are not limiting but are illustraf, 1 tive ofcompounds of this invention and the procedures for their preparation andwill serve to make fully apparent all of the compounds embraced by thegeneral formulas given above.

Example 1 A solution of 115.5 g. of thiosalicylic acid in 3.2 l. ofaqueous ethanol containing 62.0 g. of sodium hydroxide is treated with168.8 g. of 1-chloro-2-nitro-4-trifluoromethylbenzene. Refluxing for 45minutes, filtering, diluting the filtrate with water, acidifying withdilute hydrochloric acid and filtering the precipitate gives o-(Z-nitro-4-triiluoromethylphenylthio)benzoic acid, M.P. 179 180 C.

A mixture of 230 g. of theabove prepared nitro compound and a suspensionof 1550 g. of-stannous chloride dihydrate in 1700 ml. :of glacial aceticacid and ml. of Water which has been treated with hydrogen chloride gasis warmed on a steam bath for three hours, then poured into 4 Lot water.The precipitate, O-(Z-amino- 4-tritluoromethylphenylthio)benzoic acid,is filtered off, washed with water and recrystallized frometherpetroleumether. I

The above prepared amino compound (158.4 g.) in 84 ml. of sulfuric acidand 1 liter of ethanol is cooled to 2 to 0 C. and treated with 42 g. ofsodium nitrite in ml. of water. The resulting mixture is stirred at 0for 30 minutes. Ethanol (300 ml.) and 2 g. of copperbronze powder areadded. The mixture is stirred allowing the temperature to rise slowly toreflux temperature and maintained at this temperature for 1.5 hours. The

mixture is filtered, concentrated, diluted with water and filtered togive o-(4-trifluoromethylphenylthio)benzoic acid, M.P. l53154 C. Heatingthis compound (60.0 g.) for two hours on the steam bath with 200- ml. ofconcentrated sulfuric acid, cooling, pouring into water and collectingthe precipitate, dissolving it in ether, agitating the ether solutionwith 10% sodium bicarbonate, filtering, washing with water,. andevaporating the ether gives 2-trifiuoromethyl-10-thiaxanthenone, M.P.143144.5 C., after recrystallization from petroleum ether.

Magnesium (1.8 g.) and 4 ml. of dry tetrahydrofuran are warmed toreflux. Ethyl bromide (0.5 ml.) is added.

A solution of 8.7 g. of 3-chloro-l-dimethylaminopropane in 30 ml. oftetrahydrofuran is added slowly and the re sulting mixture is refluxedfor one hour. To this mixture is added 10.0 g. of2-"trifluoromethyl-IO-thiaxanthenone in 150 ml. of tetrahydrofuran andthe mixture is refluxed for minutes, then concentrated in vacuo. Theresidue is poured into ice coldwater. The solid is filteredofi andrecrystallized from aqueous ethanol to give 10-hydroxy- 10 (3dimethylaminopropyl) 2 trifiuoromethylthiaxanthene, M.P. 1l8119 C.

A mixture of 11.4 g.- of10-hydroxy-10-(3-dimethylaminopropyl)-2-trifluoromethylthiaxanthene andml. of concentrated hydrochloric acid is heated on a steam bath forthree hours.- The excess acid is removed in vacuo and the residue istreated with ether. The solid, a mixture of the cis and trans isomers of10-(3-d-imethylaminopropylidene)-2-trifiuoromethylthiaxauthenehydrochloride is isolated'by filtration. The isomers can be separated byfractionalcrystallization from acetone-ether. The hydrochlorides (cis ortrans or cis trans mixture) in aqueous alcohol solution are neutralized,extracted with ether and the extracts concentrated to give the free.bases.

-I-lydrogenation of 2.0 g. of these propylidene compounds with 0.5 g. ofpalladium-on-charcoal in ethanol solution at atmospheric pressure forthree hours gives, after filtering and concentrating,10-(3-dimethylaminopropyl -2-trifiuoromethylthiaxanthene.

Example 2 A mixture of 1.4 g. of magnesium and 7 m1. of drytetrahydrofuran is heatedto reflux, then 1 ml. of ethylpropyl)-4-methylpiperazine in 30 ml. of tetrahydrofuran. The resultingmixture is refluxed for one hour. Ten grams of2-trifluoromethyl-10-thiaxanthenone (prepared as in Example 1) and 150ml. of tetrahydrofuran are added and the refluxing is continued for onehour. Concentrating the solution and pouring the residue into cold wateryields 10-hydroxy-10-[3-(4-methyl-l-piperazinyl)propyl]-2-trifluoromethylthiaxanthene. A mixture of the above preparedhydroxy compound (8.2 g.) is heated on a steam bath with 100 ml. ofconcentrated hydrochloric acid for three hours. Evaporation of theexcess acid and treatment of the residue with ether gives10-[3-(4-methyl-1-piperazinyl)propylidene]-Z-trifluoromethylthiaxanthene dihydrochloride. Fractionalcrystallizationfrom isopropanol-ether gives the cis and trans isomers. I

The free bases are obtained by neutralizing an alcoholic solution of thedihydrochlorides with sodium carbonate,

extracting with ether and removing the ether solvent in vacuo.

Hydrogenation of 1.0 g. of the propylidene compounds in 50 ml. ofethanol with 0.3 g. of palladium-charcoal gives 10-[15(4-methyl-1-piperazinyl)propyl]-2-trifluoromethylthiaxanthene.

Example 3 2-chloro-5-trifluoromethylaniline (205.5 g.) in sulfuric acidsolution (670 ml. of acid in 1330 ml. of water) is cooled to 5 andtreated with 70 g. of sodium nitrite in 280 ml. of water. Potassiumiodide (183 g.) in 275 ml. of water is added and the resulting mixtureis allowed to stand for 16 hours, then heated at 50 C. for one hour.Extraction with ether, evaporation and distillation of the extractsgives 4-chloro-3-iodotrifiuoromethylbenzene, B.P. 74 75 C. (5 mm.).

To magnesium turnings (14.5 g.) in 100 ml. of refluxing dry ethercontaining a few drops of ethylene bromide is added 17 6 g. of4-chloro-3-iodotrifluoromethylbenzene in 900 ml. of anhydrous ether over1.75 hours. The mixture is refluxed for two hours, then cooled to 20 C.and treated with Dry Ice. Hydrolyzing at 0 C. with cold dilutehydrochloric acid, extracting with ether, washing the extracts withpotassium carbonate, acidifying the aqueous layer with hydrochloric acidand filtering gives 2- chloro-5-trifluoromethylbenzoic acid.

A mixture of 105 g. of the above prepared benzoic acid, 56 g. of phenol,69 g. of potassium carbonate, 5 g. of copper-bronze powder and 5 g. ofcuprous iodide in 500 ml. of nitrobenzene is heated at 160170 C. forfive hours. The cooled mixture is treated with an additional 70 g. or"potassium carbonate and steam distilled to remove the solvent. Theaqueous solution is acidified with concentrated hydrochloric acid togive 2-phenoxy-5-trifluoromethylbenzoic acid which is recrystallizedfrom carbon tetrachloride to give white crystals, M.P, 114115.5 C.

A solution of 82 g. of 2-phenoxy-5-trifluoromethylbenzoic acid in 500m1. of concentrated sulfuric acid is heated at 95C. for two hours. Thehot solution is poured into warm water. The white solid is collected andtreated with 10% potassium carbonate, washed with water and recrys-"tallized from benzene-petroleum ether to give white crystals (M.P.119.5120.5 C.) of Z-trifluoromethylxanthenone.

A mixture of 2.52 g. of magnesium and 7 ml. of dry tetrahydrofuran areheated to reflux, then treated with 1 m1. of ethyl bromide. 3-chloro-ldirnethylaminopropane (12.1 g.) in 50 ml. of tetrahydrofuran is addedand the mixture is refluxed for 9.0 minutes. A solution of 17.0 g. of2-trifiuoromethyl-9-xanthenone in 200 ml. of tetrahydrofuran is addedslowly and the refluxing continued one hour. Working up as inExample 2gives 9-hydroxy-9- 3-dimethylaminopropyl) -2-trifluoromethylxanthene.

Heating the above prepared compound with 100 ml. of concentratedhydrochloric acid at 8590 C. for three hours yields the hydrochloridesalts of 9-(3-dimethyl- 6 aminopropylidene)-2-trifiuoromethylxanthene(cis and trans forms).

Hydrogenation of the cis or trans propylidene (prepared byneutralizing-the hydrochloride inaqueous ethanol, extractin'g with etherand evaporating the ether extracts) using a palladium-charcoal catalystin ethanol solution at atmospheric pressure for two hours gives, afterfiltration, concentration and recrystallization of the residue9-(3-dimethylaminopropyl) -2-trifluoromethylxanthene.

Example 4 A solution or" 15.0 g. of 2-trifluoromethyl-9-xanthenone,prepared as in Example 3, in 150 ml. of tetrahydrofuran is added to 20g. of 3-(4-methyl-1-piperazinyl)propy1 magnesium chloride, prepared asin Example 2, in tetrahydrofuran solution. The resulting mixture isheated at reflux for minutes. Concentrating, then treating the residuewith cold water gives 9-hydroxye9-[3-(4-methyl- 1piperazinyl)propyl]2-trifluoromethylxanthene. This compound is heated ona steam bath with 90 ml. of concentrated hydrochloric acid for fourhours. Removing the excess acid in vacuo and triturating the residuewith ether gives 9-[3-(4-methyl-l-piperazinyl)propylidene1-2-trifluoromethylxanthene dihydrochloride.

An aqueous ethanol solution of the dihydrochloride is neutralized withsodium carbonate, extracted With ether and the ether extracts areevaporated to yield the free base. A sample of the base (1.0 g.) isdissolved in 50 m1; of ethyl acetate and treated with two equivalents ofmaleic acid. Concentration and cooling gives the dimaleate salt,

Hydrogenation of the propylidene compound with platinum oxide catalystin ethanol solution at 50 p.s.i. for one hour gives9-[3-(4-methyl-1-piperazinyl)propyl]-2-trifluoromethylxanthene.

Example 5 A mixture of 14.0 g. of Z-trifluoromethyl-lO-thiaxarithenone,made as in Example 1, and 15.9 g. of 3-dimethyl-i amino-Z-rnethylpropylmagnesium chloride, made as in Example 1, in 200 ml. of tetrahydrofuranis refluxed for 90 minutes. Working up as in Example 4 gives 10-hydroxy-IO-(3-dimethylamino-Z-methylpropyl) 2 trifiuoromethylthiaxanthene.

Heating the above prepared hydroxy compound with m1. of concentratedhydrochloric acid at 90 C. for three hours, concentrating andtriturating the residue with ether gives10-(3-dimethylamino-Z-methylpropylidene)-2 trifluoromethylthiaxanthenehydrochloride which is fractionally crystallized from acetone ether togive the cis and trans racemates.

The free bases are obtained by dissolving the hydro-. chlorides inaqueous ethanol, neutralizing with sodium carbonate, extracting withether and evaporating the ether extract.

Treating the free base with anhydrous hydrogen bromide in ether-ethanolsolution gives the corresponding hydrobromide salt.

Two grams of10-(3-dimethylamino-Z-methylpropylidene)-2-trifluoromethylthiaxantheneis hydrogenated with 0.2 g. of palladium-on-charcoal at atmosphericpressure for three hours. Filtration and removal of the solvent in vacuogives10-(3-dimethylamino-2-methylpropyl)-2-trifluorornethylthiaxanthene.

Example 6 A mixture of 200 g. of 2-benzyloxyethanol in 2 1. of pyridineat 50 C. is treated with 275 g. of p-toluenesulfonyl chloride and theresulting mixture is stirred at 0 C. for two hours. Water is addedslowly at 05 C. Extracting with chloroform, washing the extract withdilute hydrochloric acid, waterand potassium bicarbonate, andevaporating the solvent leaves benzyloxyethyl p-toluene-sulronate.

A mixture of 186 g. of the above prepared p-toluenesulfonate, 106 g. ofN-ethoxycarbonylpiperazine, 44 g. oi potassium carbonate and 800 ml. oftoluene is refluxed -furan istreated with 1 ml. of ethyl bromide.

for. 21 hours, then filtered and extracted with dilute hydrochloricacid. The extract is basified with sodium hydrooxide and extracted intochloroform. Evaporation of the chloroform and distillation of theresiduein vacuo gives 1-benzyloxyethyle4-ethoxycarbonylpiperazine, B.P. 153-156 C-.(0.15 inm.).

Hydrolysis and decarboxylation of this ester (188 g.) is accomplished byrefluxing with 155 g. of potassium hydroxide, 155 ml. of water and 1550ml. of ethanol for four days. Filtering, concentrating, adding Water tothe residue, acidifying with hydrochloric acid, heating to 90 C.,saturating with potassium carbonate, extracting into chloroform,evaporatnig and distilling the chloroform givesN-benzyloxyethylpiperazine.

A mixture of 50 g. of the above prepared piperazine, 30.1 g. of sodiumcarbonate and 200 ml. of benzene is heated to reflux and treated with39.5 g. of 3-bromopropanol over 1.5 hours. The resulting mixture isrefluxed for two hours, then filtered, extracted with dilutehydrochloric acid, basified, extracted with benzene, and

the extracts are .concentrated and distilled to give l-benzylo xyethyl-4-(Ba-hydroxypropyl) piperazine, B.P. 188+ 190 C. (0.15 mm.). Thefree base is converted to the dihydrochloride salt by treatment of analcoholic solution with ethereal hydrogen chloride to separate the salt.

Thionyl chloride (67 g.) is'added over 15 minutes to a mixture of 39.5g. of the above prepared dihydrochloride salt and 400 ml. of chloroform.Refluxing for four hours, cooling and filtering yields thedihydrochloride salt of 1-benzyloxyethyl-4 (3 chloropropyl) piperazine,M.P. 201-202 C. The salt in aqueous solution is basified. Extractionwith ether and evaporation of the solvent yields the free base.

Magnesium (1.3 g.) in 8 ml. of refluxing tetrahydro- A. solution of 22.7g. of l-benzyloxyethyl-4-(3-chloropropyl)piperazine. in 50 ml. oftetrahydrofuran is added slowly and the mixture is refluxed for onehour.

A solution of 14.0 g. of 2-trifluoromethyl-IO-thiaxanthenone (preparedas in Example 1) in tetrahydrofuran is added over /2 hour and therefluxing is continued for two hours. Removing the solvent in vacuo,pouring the residue into ammonium chloride in cold water and filteringgives -[3-(4-benzyloxyethyl 1-'piperazinyl)propyl']-10-hydroxy-2-trifluorornethylthiaxanthene.

I Dehydration and debenzylation of the above prepared hydroxy compoundby treating with concentrated hydrochloric acid at 90 C. for-five hoursgives a mixture of cis and trans isomers of10-[3-(4-hydroxyethyl-1-piperazinyl)propylidene]-2-trifluoromethylthiaxanthene dihydrochloride. Separationof the isomers is accomplished by fractional crystallization fromethanol-ether.

The. free bases are obtained by dissolving the cis, trans or mixturethereof of the dihydrochloride salts in aqueous ethanol, neutralizingwith sodium carbonate and extracting with chloroform. The chloroformextracts are concentrated' and distilled to give the10-[3-(4-hydroxyethyll-piperazinyl) propylidene]-Z-trifluoromethylthiaxanthene.

Example 7 A mixture of 2.1 g. .of a cis-trans mixture of 10-[3-(4-hydroxyethyl 1 piperazinyl)propylidene] 2 trifluoro-'methylthiaxanthene,made as in Example 6, and ml. of benzene is treatedwith a solution of 1.0 g. of acetyl chloridev in 15 ml. of benzene.Refluxing for 30 minutes, cooling and concentrating in vacuo gives, asthe residue, crude 10-[3-(4-acetoxyethyl-l-piperazinyl)propylidene] 2trifluoromethylthiaxanthene dihydrochloride which is fractionallycrystallized from ethanol-ether.

Example 8 To. a mixture of 43.4 g. of 10-[3-(4-hydr-oxyethyl-1-piperazinyDpropylidene]-2 trifluoromethylthiaxanthene dihydrochloride,madeas in Example 6, in 400 ml. of chloroform is added 67 g. of thionylchloride over 15 minutes. The resulting mixture is refluxed for fourhours, cooled and filtered to give 10-[3-(4-chloroethyl-l-piperazinyl)propylidene]-2-trifluonomethylthiaxanthene dihydrochlo- I ride. The-freebase is liberated in benzene solution by the addition of aqueouspotassium hydroxide, separation of the organic layer and drying.

Sodium (4.9 g.) is added to 203 g. of dry ethylene glycol at 6070 C. Tothis mixture is added the above prepared chloroethylpiperazinyl compoundin benzene solution at C. over 30 minutes. The benzene is removed andthe'residue is stirred at room temperature for 18 hours. Waterv isadded. The organic layer'is separated and extracted into dilutehydrochloric acid. The aqueous extract is basified with sodium hydroxideand extracted With benzene. The benzene is removed in vacuo, leaving10-[3-(4-hydroxyethoxyethyl 1 piperazinylpropylidene]-2-trifluoromethylthiaxanthene.

The dihydrochloride salt is obtained by treating an alcoholic solutionof the free base with ethereal hydrogen chloride.

Example 9 A mixture of 5.0 g. of 10-[3-(4-hydroxyethyl-1-piperazinyl)propylidene1-2 trifluoromethylthiaxanthene dihydrochloride, prepared asin Example 6, and 25g. of thionyl chloride in 75 ml. of chloroform isrefluxed for six hours. Removal of the solvent in vacuo gives10-[3-(4-chloroethyl-l-piperazinyl)propylidene] 2trifluoromethylthiaxanthene dihydrochloride.

A mixture of 20 ml. of B-hydroxyethyl ether in 20 ml. of dry benzene istreated with 0.5 g. of sodium. The chloro intermediate prepared above(converted to the free base by .the procedure of Example 8) is added andthe mixture is heated on a steam'bath for three hours, then stirred atroom temperature for 18 hours. Water is added and the mixture isextracted with benzene. Extraction of the benzene solution with diluteacid, neutralization of the acid extracts, extraction with chloroformand evaporation of the chloroform extractv gives,10-[3-(4-hydroxyethoxyethoxyethylpiperazinyl)propylidene] 2trifluoromethylthiaxanthene.

Example 10 A mixture of 3-pyrrolidinylpropyl magnesium bromide (preparedby refluxing for one hour 2.6 g. of magnesium and 19.2 g. ofN-(3-bromopropyl)pyrrolidine in tetrahy rofuran) and 13.2 g. of2-triflu0r0n1ethyl-9-xanthenone (prepared as in Example 3) in ml. oftetrahydrofuran is refluxed for 90 minutes. Removal of the solvent invacuo, treatment of the residue with cold water and filtration gives9-hydroxy-9-(3-N-pyrrolidinylpropyl) -2-trifluoromethylxanthene.

Dehydration of this hydroxy compound by heating with 90 ml. ofconcentrated hydrochloric acid on the steam bath for four hours yields amixture of cis and trans 9-(3-N-pyrrolidinylpropylidene)-2-trifluoromethylxanthene hydro-chloridewhich is fractionally crystallized from ethanolether. The free base isobtained by neutralizing an aqueous-ethanol solution of thehydrochloride, extracting with ether and evaporating the ether extract.

The propylidene compound (4.0 g.) in ethanol solution is hydrogenatedwith-0.5 g. of platinum oxide at 50 p.s.i. for two hours to give, afterfiltering and concentrating in vacuo,9-(3-N-pyrrolidinylpropyl)-2-trifluoromethylxanthene.

An ethyl acetate solution of the free base is treated with an equivalentamount of citric acid to give, upon concentration andcooling,9-(3-N-pyrrolidinylpropyl)-2-trifluoromethylxanthene citrate.

Example 11 I Twentygrams of Z-trifluoromethyl-lO-thiaxanthenone,prepared as in Example 1, in 200ml. of refluxing isobutyl alcohol istreated with 10.0 g. of sodium. The resulting mixture is refluxed for 30minutes and the excess alcohol is steam distilled. The residue iscooled, diluted with cold water and filtered to give2-trifluoromethy-lthiaxan- A mixture of 25.0 g. ofZ-trifluoromethylxanthene, prepared by refluxing2-trifluoromethyl-9-xanthenone in isobutanol containing sodium as inExample 11, 17.8 g. of 3-chloro-1-diethylamino-2-methylpropane, 5:8 g.of potassium amide and 100 ml. of benzene is refluxed for eight hours.Working up as in Example 11 gives9-(3-diethylamino-2-methylpropyl)-2-tnifiuoromethylxanthene.

Example 13 A solution of 13.2 g. of Z-trifluoromethyl-9-xanthenon'e,prepared as in Example 3, in tetrahydr-ofuran is added over one hour to16.0 g. of 3-(4-1benzyloxyethyl-1-piperazinyl) propylmagnesium chloride,prepared as in Example 6, in tetrahydrofuran while gently refluxing.Refluxing is continued for two hours. Concentrating, pouring the residueinto ammonium chloride, ice and water, extracting with ether,evaporating the extracts and treating the residue with concentratedhydrochloric acid at 95 C. for one hour gives a mixture of cis and trans9-[3-(4-hydroxyethyl 1 piperazinyDpropylidene] 2 trifluoromethylxanthenedihydrochloride. Fractional crystallization from ethanol-ether separatesthe isomers. The free bases are obtained by neutralizing an aqueoussolution of the dihydrochloride, extracting into ether and evaporating.the ether in vacuo.

Hydrogenation of the propylidene compound in acetic acid solution withpalladium-on-charcoal at 50 p.s.i.' for two hours gives9-[3-(4-hydroxyethyl-l-piperazinyDpropyl] -2-trifluoromethylxanthene.

Example 14 Phenyl chlorocarbonate (1.9 g.) is added to a solution of 4.2g. of 9-[3-(4-hydroxyethyl-l-piperazinyDpropylidene]-2-tr-ifluoromethylxanthene, prepared as in Example 13, in 25 ml.-ofanhydrous pyridine with stirring. After 15 hours at 25-30 C., water isadded and the mixture is extracted with chloroform to give, afterconcentration of the extracts, the phenylca-rbonate of9-[3-(4-hydroxyethyl- 1-piperazinyl)propylidene]-2-trifluoromethylxanthene.

A solution of this phenylcarbonate in 50 m1. of anhydrous ether is addeddropwise to 100 ml. of liquid ammonia with stirring. After hours thereaction mixture is treated with water and extracted with ether. Theether extracts are washed with dilute sodium carbonate solution, driedand concentrated in vacuo to give9-[3-(4-carbamoyloxyethyl-l-piperazinyl)propylidene] 2trifluorornethylxanthene. v

The free base .is converted to the dihydrochloride salt by treatmentwith ethanolic hydrogen chloride.

Example Treatment of 9 [3 (4 hydroxyethyl-l-piperazinyl) propylidene] 2-trifluoromethylx-anthene, prepared as in 10 pip erazinyDpropylidene]-2-:trifluoromethylxanthene tained.

A mixture of 2.0 g. of 9-[3-(4-dimethylcarbamoyloxyethyl-1piperazinyDpropylidene] 2 trifluor-omet-hylxanthene, 0.4 g. ofpalladium-on-charcoal and 50 ml. of ethanol is hydrogenated at 50 psi.for two hours. 'Filtration and removal of the solvent in vacuo gives 9-[3(4- dimethylcarbamoyloxyethyl-l-piperazinyl)propyl] -2trifluoromethylxanthene.

Example 16 A mixture of 14.0 g. of 3-trifluoromethyl-IO-thiaxanthenone[prepared by reacting thios-alicylic acid with 1- isobchloro-Z-nitro-S-trifluoromethylbenzene, reducing the re- 7 sultingo-(2-nitro-S-trifluoromethylphenylthio)benzoic acid, deaminating byd'iazotizing the resulting o-(2-amino-5-trifluoromethylphenyl-thio)benzoic acid and treating with ethanol, andcyclizing by heating with concentrated sulfuric acid] and 14.5 g. of3-dimethylaminopropyl magnesium chloride (made as in Example 1) in 200ml. of tetrahydrofuran is refluxed for minutes. Concentrating, pouringthe residue into cold water and filtering yields 10hydroxy-10-(3-dimethylaminopropyl) 3 trifiuoromethylthiaxanthene.

Treatment of this hydroxy compound with ml. of concentrated hydrochloricacid on a steam bath for three hours gives-10-(3-dimethylaminopropylidene)-'3-trifluoromethylthiaxanthenehydrochloride. Fractional crystallization from acetone-ether separatesthe cis and trans isomers.

The free bases are obtained by neutralizing aqueous solutions of thehydrochlorides, extracting with ether and evaporating the etherextracts.

Hydrogenation of the propylidene compound in ethanol using apalladium-charcoal catalyst at atmospheric pressure for three hoursgives IO-(S-dimethylaminopropyl) -3-trifluoromethylthiazanthene.

Example 17 A mixture of 13.0 g. of 1-trifluoromethyl-9-xanthenone(prepared by the procedure of Example 3 from Z-chloro-6-trifluoromethy1aniline) and 20.0 g. of 3-(4-methyl-1-piperazinyl)propyl magnesium chloride (prepared as in Example 2) in 200ml; of tetrahydrofuran is'refiuxed for one hour. Working up as inExample 16 gives 9-hydroxy-9-[3-(4-methyl-1-piperazinyl)propyl] 1trifluoromethylxanthene. Dehydration by treatment with concentratedhydrochloric acid gives 9-[3-(4-methyl 1 piperazinyl)-propylidene] 1trifluoromethylxanthene dihydrochloride which is fractionallycrystallized from acetoneether.

Neutralization of an ethanol solution of the dihydrochloride saltfurnishes the free base which is hydrogenated using a palladium-charcoalcatalyst as in Example 4 to give9-[3-(4-methy1-l-piperazinyl)propyl]-1-trifluoromethylxanthene.

Example 18 Seven grams of 4-trifluoromethy-l 1O thiaxanthenone [preparedaccording to the procedure of Example 1 from thiosalicylic acid and2-chloro-l-nitro-3-trifluoromethylbenzene which is made by fluorinating2-chloro-3-nitrobenzoic acid with sulfur tetrafluoride, J. Am. Chem.Soc. 81: 31656 (1959)], and 10.0 g. of S-dibutylaminopropyl magnesiumchloride (made by the procedure of Example l) in 100 m1. oftetrahydrofuran are heated at reflux for 90 minutes. The reactionmixture is worked up as in Example 16 to give 10-(3-dibutylaminopropyl)-10-hydroxy-4-trifluoromethylthiaxanthene.

Dehydration of the hydroxy compound by heating with concentratedhydrochloric acid at 85-90 C. for three hours gives10-(B-dibutylaminopropylidene)-4- trifluorornethylthiaxanthenehydrochloride.

Hydrogenation of the free base (prepared by neutralizing an ethanolsolution of the hydrochloride with sodium carbonate, extracting withether and evaporating the extracts) in ethanol solution with a platinumoxide cata- 1 1 lyst gives -(3-dibutylaminopropyl) 4trifluoromethylthiaxanthene.

Example 19 A mixture of 26.6 g. of 2-trifluoromethylthiaxanthene(prepared as in Example 11), 20.9 g. of 1-formyl-4-(3-chloropropyl)piperazine, 4.1 g. of sodium amide and 200 ml. of tolueneis refluxed for eight hours. Diluting with water, neutralizing,separating the organic layer and distilling in vacuo gives10-[3-(4-formyl-lpiperazinyl)propyl] -2-trifluoromethylthiaxanthene.

A mixture of 5.0 g. of the above prepared N-formyl compound is heated atreflux with 2 ml. of 40% sodium hydroxide and 100 ml. of aqueous ethanolfor minutes.

Concentrating, treating the residue with benzene and water, andevaporating the benzene layer gives, as the residue, 10-3-N-piperazinylpropyl -2-trifluoromethylthiaxanthene.

Refluxing 3.9 g. of the above prepared N-piperazinyl compound with 0.44g. of ethylene oxide in methanol solution for two hours, thenevaporating the solvent in vacuo leavesv 10-[3-(4-hydroxyethyl 1piperazinyl)propyl]-trifluoromethylthiaxanthene.

The above prepared hydroxyethyl compound in benzene solution is refluxedwith an excess of acetyl chloride for minutes to give, after cooling andconcentrating, 10-[3-(4-acetoxyethyl-1-pipcrazinyl)propyl] 2trifiuoromethylthiaxanthene dihydrochloride.

What is claimed is:

1. A chemical compound of the class consisting of a free. base and itsnontoxic, pharmaceutically acceptable, acid addition salts the free basehaving the formula:

i O F s I EHCH GI-IZN N-alkyl in which the alkyl moiety has 1 to 4carbon atoms.

3. A chemical compound having the formula:

S I l OF3 alkyl (3H omomN alkyl in which the alkyl moieties have 1 to 4carbon atoms.

4. A chemical compound having the formula:

V l O.

\/ 3 alkyl H GH C HzOH N alkyl in which the alkyl moieties have 1 to 4carbon atoms.

5. A chemical compound having the formula:

11 JHZCH OH N N-alkyl in which the alkyl moiety has 1 to 4 carbon atoms.

6. A chemical compound having the formula:

\ GBICH CH N alkyl in which the alkyl moieties have 1 to 4 carbon atoms.

7. A chemical compound having the formula:

CFs

ll CHCH CH N N-alkyl in which the alkyl moiety has 1 to 4 carbon atoms.

'8. A chemical compound having the formula:

alkyl in which the alkyl moieties have 1 m4 carbon atoms.

9. A chemical compound having the formula:

H CH; C H 0 HzN\ Nalkyl References Cited by the'Examiner UNITED STATESPATENTS 1/ 60 Ullyot 260268 3/60 Gules-ich et al 260268 6/60 Bonvicinoet al 260-268 8/ 60 8/ 61 12/63 Sprague et a1 260'328 Schaeren et al260-268 X FOREIGN PATENTS 3/57 Belgium.. 9/58 Belgium.

(Other referenceson following page) Sprague et al. 260--268 13 OTHERREFERENCES Petersen et al.: Arzn. Forsch, vol. 8, No. 7, pages 395- 397(July 1958).

Yale: Journal Medicinal and Pharmaceutical Chemistry, vol. 1, pages121-123 (April 1959).

Yale: American Chemical Society, Abstracts of Papers, 134th meeting,page 8-Q, sub-topic 15, Monday afternoon (received August 25, 1958).

14 Yale: Jcurn. Medicinal and Pharmaceutical Chemistry, vol. 1, pages121133 (1959).

Winthrop et al.: Journal Organic Chemistry, vol. 27, pp. 230-234 (1962).

NICHOLAS s. RIZZO, Primary Examiner.

WALTER A. MODANCE, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,192,204 June 29, 1965 Paul N. Craig et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, lines 20 to 36, the upper right-hand portion of the formulashould appear as shown below instead of as in the patent:

column 3, lines 3 to 17, the lower right-hand portion of the formulashould appear as shown below instead of as in the patent column 12,lines 31 to 38 the formula should a below instead of as in the patent:ppear db SHOW} alk 1 H CH CH CH N y 2 2 2 alkyl Signed and sealed this7th day of December 1965.

(SEAL) Attest:

ERNEST w. SWIDER DWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITSNONTOXIC, PHARMACEUTICALLY ACCEPTABLE, ACID SOLUTION SALTS THE FREE BASEHAVING THE FORMULA: